Okay, great. We have everyone here. So thank you all for joining us today. We're really excited to have an amazing panel here to talk about the emerging pipeline for oncology treatments. With a look ahead to the upcoming ASCO conference. We're also going to touch on a few important trends related to patient care, for example, future directions and clinical trial designs, and some positive developments regarding cost and competitive competitiveness of IO agents to patients. So I'm really pleased to be joined today by this terrific panel, including Dr. James Gali, who's the chief of the GPU malignancies branch of the National Cancer Institute, and an expert in immuno oncology, Dr. Sally church science writer who is focused on oncology new product development. Umer Rifat, who is one of the top biased biotech analysts on Wall Street. And Dr. Alex Philippa Vich, a practicing oncologist who is advancing novel cancer medicines, and we're very lucky to be working with.
For today's discussion, we're going to spend the first 30 to 40 minutes hearing from the panel, and the last 20 to 30 minutes, we're going to bring up experts from the audience and I see a lot of experts in the audience. So really excited to hear from them as well.
We're going to kick off by targeting by talking about some of the targets that are generating the most interest. Clearly, there's been a lot of buzz around LaGG, three tigit and K Ras. I'm curious to hear from you, Umer, do you think the excitement is justified? Is like three overshadowing tigit, this year after having been on a sort of slow burner? And what are your thoughts on k Ras with the recent Amgen rottie and other data coming out? We're to start with you, Umer. And then we're gonna go to Alex.
Sure. I actually don't think so. I think LaGG three data is fairly underwhelming and I say that because look at the randomized trial bristles putting out it's got a hazard ratio of point seven five on PFS, that's great, but really, you got to think about in the context of standard of care nivo if the tracks at 11.5 months in checkmate, oh six seven trials, the standard of care, look at where nivo plus LaGG three tracking I think was around 10 months. So no and even if you sort of talk to Bristol Myers on this topic, like really their positioning this LaGG three combo where nivo ap does not get us really more on the B RAF, mek side, etc. So I think that was underwhelming. In fact, it was another abstract from Merck, where they put it they took a PD one plus LaGG three on their side in microsatellite stable colorectal cancer, I think was a 6% response rate. So I personally thought it was fairly underwhelming. tigit remains the big focus not just because Roche had a ridiculous hazard ratio in a randomized first line lung cancer trial and again, was lung cancer. But also because now there's a second high profile randomized trial and tigit coming up for gilliat arcus. That's in specifically in PDL, one super highs about 50%. And, and data is imminent. There's differences in the FC backbone between arcus versus the rotated, but I won't bore you with that. I'll turn it back to you.
Thanks, Sally. Alex, do you want to comment on tigit k Ras and like three?
Sure. Thank you, Daphne. So I hear you rumor with your comments around LaGG. Three, I think from a clinicians point of view, I'm just trying to think about how we're balancing efficacy and toxicity. And we all know that anti PD one anti ctla combos can give us some significant talks in patients and we are limited as to how long we can use anti ctla four agents in this combination. So I was intrigued by the data in the lack three anti PD one combination that came out from regeneron.
And what struck me there is what are we actually trying to achieve with this particular combination of LaGG three PD one. And what what at least comes across to me is that we're intending to expand the population of checkpoint inhibitor responders. And what struck me in the regeneron data or family mob, and libertario is the response rate of just north of 60%. With some complete responses, many partial responses are baked in 33 patients, but then we have and that impatience without any prior exposure to checkpoint inhibitors and compare that to the response rate of about 13% that they got in patients that had prior checkpoint inhibitors. It's quite a stark contrast as to, but perhaps guiding us how to select patients for LaGG three PD one combos, and then also to think about whether this particular combination is safer than ever
PD one ctla four. And then also think about some other
LaGG. Three assets, such as the one coming from a new tab that potentially has, is modulating a different function of LaGG, three outside T cells, which I think is something that digit and LaGG. Three as targets have in common, both for drug developers, and clinicians. And certainly, I'm hoping on the investor side, because we are ideally wanting at targets and then assets aimed at those targets that are able to target more than just T cells. And tigit I think was a nice poster child there. And got a lot of attention last year at ASCO and other conferences, because it does have a play on NK cells, and LaGG, three potentially may have a play on dendritic cells, as well as new tech there is advocating with their fusion protein fuse to idg. One, that it is an MHC type two agonist and an antigen presenting activator. So I think that we're going to continue to see data there and hopefully be able to tailor the patient population a little bit better. But I'm excited as a clinician to have a choice on the combinations. So it's no longer just anti PD one ctla. Four, but we now do have a spectrum to choose from.
Thank you, Alex, Sally, and James, would you like to comment on those three targets? Or on what's just been said?
So I will just say that I agree with Alex and, and with Umer, that, you know, first of all, it's nice to have more options that were are coming into the clinic. I think there's more that needs to be done to see where this is going to end up.
I think there's there's lots of potential for combination approaches down the road. And I am interested to see where it's going to end up.
Thank you. James, Sally, did you want to add anything?
Um, I think the lexx three resulted some ways were a little bit of a surprise bearing in mind, most of the agents we've seen before in page one were pretty disappointing. There were few responses in any truck driver actually. Not much toxicity either. So I think the certainly the read that limit data look very encouraging. regeneron looks to be coming along nicely. I agree with what everybody said, but the concern I have Ridge which trimmer tarps are they going to end up having activity in? I mean, we've got a knife Daedra melanoma, even if we had a replacement for say, ctla. Four? In that indication? I think that would be a big advance. But where it goes beyond that, maybe we know maybe others, I think it remains to be seen what the full opportunity will be beyond melanoma.
And I think also, if you look at the data that we have, so far, it's tracking the one year data for checkmate 57 in terms of rough compatibility. So I think that gives us some hope that the three year and five year landmarks are viable, that we might have a replacement for the niveaux epi but with fewer toxicities. And I think that's an encouraging start, but still not wait and see what happens. teach it, I worry, we'll end up like what we saw in non small cell lung cancer we've met met up a few years ago, where you get encouraging phase one, phase two data, and then we come to the phase three trial, and it all fizzled out.
I have concerns about that with tigit. And I think there are also differences in terms of the various molecules, do you need an active fg or not? If you have a sine of one, will you still get the same results? So I think tivities a lot more uncertain, and a lot yet to learn about that. And same thing with TGF beta. It's a complicated pathway, which part of the pathway should we be best targeting? And I think it's a lot more uncertain on both of those fronts. But actually, there were some very nice TGF beta data at ASCO, very early phase one in triple combinations, which I'm sure James will talk about later, but there was an issue
Shifting molecule from Novartis that had a different approach with less toxicity. So it's early days, but I think there's still lots of encouragement to go there yet.
Thanks, Sally. By the way, for those of you who are new to clubhouse, there's a feature that on clubhouse, which is if you want to clap, you just hit your mic back and forth a bunch of times. So that's that. We know that one speakers copy for another. The other thing I wanted to mention is that we're trying to record this, this panel, and if we are able to do that successfully, we'll make it available as a follow up. I'm not 100% sure. But just in case, I'm saying that for legal purposes, we might end up recording. Okay, very good. So let's keep going with some of these targets. And I think moving towards SHP2, which both Umer and Sally seem to be disappointed with. And you guys had differing opinions on MacroGenics, etc. So Umer was more bullish than Sally, maybe Sally, you can start kick us off on this one. And then I'd love to hear from Umer.
Okay, well, I guess my concern is, number one, we know that the target is expressed in many cancers, and it has limited expression in normal cells, which is great. The downside is just because the target is overexpressed, doesn't really matter to the survival of the cancer. So it could be a marker as opposed to a target. And what we learn is that the case here, there is some evidence, from my point of view, in favor, but if you look at the data on ASCO, last year, they had a couple of stable disease in I think, multiple so Kosti, but no objective responses to get tivity was, but visitors escalation trial. So you wait for longer follow up. This year, we still have to staple disease, totally different tumor types are what happened to the over two, on one on confirmed passive response awfully this year in melanoma. So if you are looking at it from an industry perspective, for phase one trial, we normally look for activity, the range is about 10%. So in a 30 patient trial, you're looking for three partial responders in order to move forward. It's a typical ballpark figure, even if you can consume. Even if you assume that the partial response is confirmed, one out of 29 is three and a half percent. So from my perspective is way lower than the threshold we would use for the shooting the next level, so my concern is that we're actually looking at a marker of tumor expression as opposed to a genuine target. But I can't be wrong. So over to you and I'm quite happy to be out in deals away.
I'm perhaps on my end, I guess. First kicking it off on ship to well, actually let me start with the seven H three because that's where Sally left it off on V seven h3 antibody drug conjugate. here's here's sort of how I see it on data this year. Is there any responses? Yes, there is. There is a there is a there is a partial response in melanoma. Is it confirmed? Well, in the abstract, it didn't look like it in the company's press release. So technically, we have a confirmed response in melanoma out of how many people well out of three people in that cohort 630 reported. So that's point number one. So two stable disease, one partial response with a B 73. ABC. Okay, fair enough. What else do we have? Well, well, last year, we didn't have any resist responses in in prostate. Well, we did have was was a bunch of PSA was was a bunch of responses on PSA metrics. And I think that's continued to be the case. And in fact, there are now reporting six months plus durability on the PSA 50 so it looks like they have activity you might ask well, how come they don't have any responses in prostate and I think part of the problem was all the data they reported previously was not racist valuable to you. So we couldn't expect that and for those reasons, it seems to be quite interesting in my opinion on ship to I think this one unfortunately, I had a lot of hope for this but it's looking it's it's it's consistently underwhelming. So let me start with this one. Novartis has now dosed over 400 patients best I could tell on Clin trials.gov if they finally three years in which is highly unusual for cancer setting three years and they finally put out a press release, sorry, the abstract which has, I believe that 128 patients in the abstract yesterday, zero responses. I think that's very underwhelming, especially considering the Sanofi revolution ship to they had at least one car and a PR in a different setting in the car, I think was in G 12. c setting, but they have a couple of actual confirmed responses. I mean, that's not a blowout number response rate, but there was
Something signal. newborns didn't necessarily have that either. That coupled with the fact that there was another company called Jacob bio, I don't know that company well enough, but they had sort of experimented with a couple of ship twos, and they ended up giving it up to abbvie for less than 100 million upfront kind of tells you everything and it looks like ship two's looking underwhelming, especially if you paired with the fact that Amgen is running six arms in their in their face to chaos combination trial. So not a coincidence, Amgen only talking about mek and EGFR being the two combos they want to report this fall not shipped to not many others, including herb, etc. So I'll pause there.
Right. Yeah, I think Alex, you wanted to comment.
Yeah, I just wanted to add something that caught my attention when it comes to the macro genix v seven h3 assets in terms of talks. And while we know this is an ADC, and I'm not too surprised to see neutropenia is and fatigue and some gi talks. But what caught my eye in this abstract is actually some skin talks, that is a little bit higher than I would expect for this particular asset. Then we're actually seeing palmoplantar aerator this stasia, not every Thema, but every through this stasia. And then we're seeing skin pigmentations and pruritus, and maculopapular, rash, and all of this in double digit percentages. So that just gives me pause as a clinician as to how this may be received by patients because we have a vast experience with EGFR targeted agents that are very famous for skin talks. And we all know how that plays out in clinic. So this is just a moment of pause for me for this particular asset, then perhaps similar ones in the class targeting this particular molecule.
Make sense. James, can you talk about ventral first alpha and some of the other NCI programs that you guys are working on? It sounded like you were intrigued by data from a couple of different studies there.\
Yeah, absolutely. So, you know, let me first start by saying ventricular alpha, for those who aren't familiar with it is this anti PDL? One antibody that has on the FC portion of the antibody to TGF beta receptors that serve as a TGF beta receptor trap. The idea is it binds to areas that are PDL one high and can see Quester the TGF beta in those areas at any activated TGF beta. And it does so with all three isoforms TGF beta one, two and three. So this is a agent that's made by MD Serrano or Merck, kgaa, Darmstadt, Germany, and they are working in collaboration with GSK for the development of this agent. Now, in January, there was a press release saying that they were stopping the lung cancer study in frontline lung cancer and PDL one Hi, cancers. This was a randomized study, comparing venturefest alpha to
Pember lism ab and PDL one high, so that's 50% or more based on the the approved FDA approved indication in frontline lung cancer. So we don't know we don't have the data for that. But I would just want to bring up a couple of points there. And the couple of points are number one, this is an area that is kind of playing on Pember lism Ab terps of if you're going to go against the giant in the field and fight in their own turf that may be a difficult place to to fight. In other words, it's going in PDL one Hi, could there be more benefit if if you're going to see the in PDL one low, where you have more of the impact of the of the TGF beta side of the molecule. It'll be interesting to see what the objective response rates are between the arms.
The other thing I would say though, is that the second thing I would say rather is that the patients were enrolled by lung cancer docs and these lung cancer Doc's are used to giving Pember lism ab they know the toxicities. TGF beta inhibition has some other toxicities, including skin toxicities like character, a cam film of these these small lesions that that typically don't need treatment and are cosmetically an issue in some patients. But it also maybe some low grade bleeding. But I'm interested to see what the discontinuation rates are and if that could explain for you The lack of superiority that caused them to stop the study earlier. And in terms of other programs in lung cancer, they have a specific like trial. So it's compared with the Pacific regimen versus been refused alpha with concurrent chemo radiation followed by venture fuse alpha in the stage three lung cancer, that will take a long time to read out. So I don't think we're going to have any readout to that soon. I will just say the other thing that there was a press release
just about a month ago, and biliary tract cancer with second line and beyond having an objective response rate of 10.1%. And this is compared with the and again, this was second line and beyond this was compared with 5.8% with Pember lism, AB and all comers, including frontline. But that was not the same trial that was on previously published data. So I think there certainly is interesting evidence of activity there. What we are seeing and what we published late last year was a study where we were looking at HPV associated malignancies about 59 patients and we saw that there was a 30 to 35% objective response rate, including in cervical cancer and just to put this in perspective, with PDL, one positive Pember lism of cancers and cervical cancer 14.6% of patients had objective responses on Pember lism AB, which is the on label indication for Pember lism ab in cervical cancer, so I may be HPV associated cancers are going to be a better area of interest for bid refused alpha. I think it's going to be a great agent for combination studies. There are currently 20 different studies ongoing at the NCI, many of them in combination with other IO therapies. And one of them is going to be presented at ASCO
and happy to talk about that this is a this is a study were actually pretty interesting study in HPV associated malignancies, where patients are getting a HPV specific vaccine targeting HPV 16 antigens that are expressed in the tumor along with the ventral fuse balfa. And with a tumor targeting cytokine called nhsi. Il 12. So this is a cytokine that, that targets areas of necrotic tumor that brings with it a payload of this aisle 12. And I see one of one of the people in the audience here that Dr. Chris here, he helped bring this agent into the clinic. And and along with a bunch of yourself here at the end, NCI. Yeah. What is interesting about this combination is that it's showing early data now, only in the initial abstract that will be updated at the presentation at ASCO. But in the initial abstract 14 patients 10 out of 14 have objective responses for 71% objective response rate 90% of them ongoing at a meeting of five months follow up. And what's to me more interesting is that in the PD, one refractory patients, five out of eight of them have had responses and that's pretty impressive. Typically, what we are seeing with PD one refractory patients is a response rate of 10% or less.
Thanks, James and Sally. Alex, would you like to comment on a event?
I think the triple combination looks really quite promising. I mean, early days yet. There's a small number of patients but when we think about the monotherapy with pinborough, I think about the the age of vaccine had that doubled from maybe 14% or 33%. And then we got some slightly higher results with of interest but I think the triplet looks really intriguing. And I think the addition of the cytokine could well make a difference. If you think about the data with the eye I show with with I think Pembroke or niveaux I can't remember for the clearly the cytokine makes a difference in terms of attracting more t shirts in and I think this should be wonderful. Watch out for.
Thank you, Umer, you talk to investors all the time, and we'd love to hear from you. What are other targets of interest to investors? And also, what other disappointments did you have? in sort of looking at? I understand the conference hasn't happened yet, but looking at the abstracts, and what are you hoping to see that you didn't see?
Yeah, I mean, look, if I step back and sort of think about where is the investor and investor interest most focused across oncology right now, even just stepping aside from ASCO, I guess, on ASCO itself, probably more so on macro genomics, and perhaps that Black Diamond data set update, that's probably two of the more prominent ones. But in terms of across the, across the board, like what are the big needle moving things investors are focused on? Clearly that tigit readout coming up for arcus Galia, it's really important randomized trial and first line lung cancer. That's one, I would argue immunomedics, the antibody drug conjugate tournelle V, they have an HR positive restaurant coming up in second half of the year. There's a fair amount of controversy on that now because the perception was that antibody drug conjugate does six and a half months PFS versus I don't know a couple months for where the chemo should track until we found out that the data majority from six and a half it went more towards 5.8 months. And then within the 5.8 the disclosure we never got from you in immunomedics was cDk four six experience patients where the PFS was actually 3.7 months. That's a lot of the new information has come out in papers since immunomedics acquisition. So now we're dealing with heading into a lower high profile HR positive press study with PFS tracking closer 3.7 months for ga Lv and compared to chemo might be I don't know, two and a half, three months. So how significant is that? Galia spent $21 billion on that company and HR positive breast has at least half of the pro forma sales model down. So that's number two. And I think the third one is possibly could the cd 47 phase one be data from Gilead form the basis of a registrational filing and MDs settings inside in combination, but it's another one that's getting a lot. So those are a few perhaps off top? And of course it goes without saying all the carriers combo data is certainly a lot of investor interest. I do think the expectations have pulled back in quite a bit. Certainly on the PD one synergy and shouldn't be too surprising. pd ones are never synergistic with a lot of targeted therapies. You can go to EGFR or ALK. You can go to B RAF mek it's it seems to be a pattern. So that's where sort of the investor competitions right now, in terms of things that were less than positive. I would argue perhaps third data, for example, Lilly surd had no monotherapy responses. Sanofi surd have this abstract suggesting I think 32% response rate. But if you if you look at the data closely, it's cDk four six combination. And the question you got to ask yourself is how much should a standalone cDk four six do in that setting?
And we know I think it was we know i think was monark one trial run by Lily were cDk for six monotherapy. And more advanced patients more power chemo did at least 20%. So I thought thirds were somewhat underwhelming, in my opinion. And I mentioned investors and then and then I saw there were a couple other targets that do get attention in the past like cd 73 get some attention, but there was a treatment adverse event related deaths on AstraZeneca, cd 73 there was a PARP plus PD one combination checkmate nine KB, I felt that was somewhat underwhelming. And then I didn't know what to make much of the Beijing tigit plus PD one. It was one response out of 10 patients, but it was a basket study at a lower dose. But um, so either way, I'll pause there.
I'd love to hear from Sally, also, first of all on what you were excited about, and also what was disappointing, but also kind of taking a step back. It's been interesting to hear, you know, for example, when we looked back on a car people, a lot of people were sort of disappointed. On the investment side, you know, they were saying nothing, nothing much came out of a car. But I think you had a very different perspective, a lot of some of the clinicians and scientists, so maybe you can comment on that. So first, what anything else about the ASCO abstracts that you wanted to mention that stood out to you? And then second, what are some novel and exciting targets which are currently under the radar screen in your mind?
I think the thing that I'm most looking forward to hearing about at ASCO this year is the initial will be boring to a lot of the inverted but a labyrinth in early stage breast cancer. We talk about data in first line metastatic disease which was quite dramatic. And I'm thinking that hasn't changed the data. So we don't even have an abstract chair. So I have no idea what it will look like but In my view, it needed to be really great, but really disappointing. And you can never tell what asker plenaries because they do sometimes put negative trials in there. Almost poor and cozy leave literature. But sure, I'm hoping there's a positive trial. And I hope but the data is quite dramatic. I think the interesting thing as a segue from Asia to Africa, where she stood, she typically validated back, it went away for a while, it came back, it went away.
It's kind of par for the course with the target pathway. So what was interesting, anything emerging idea of different pop targets, because the currently approved one will cut target part one to show the idea that we might be able to start hitting some of these other pop targets like pop 14, pop seven in different tumor types, I think is interesting, especially if there is an immunogenic element to it. So that we can potentially start pocketing tumors that for want of a better word are less immunogenic, but can be stimulated, who achieve lasting pathway using a PARP inhibitor in combination for I think there was that the other side is if we know the part to infuse, she is Milo suppression. So if we can get rid of that and only target part one and have a more selective inhibitor inhibitor, I think that will be a really exciting for future combinations motor, perhaps many people will realize so there are some in development.
On the other side, in terms of other targets that people are probably not watching. There is there was some very nice data in liver cancer, actually, on the gamma delta t shows HR published, which was an E publication work, it was an interesting idea where you could use gamma delta t allergen or gamma delta T cells with a cytokine to have some effect in a tumor type are really we need we still need more help off. And I'm going to throw the ball, Alex, on that one because he has an interest in this area, but also rich condition in terms of what could this mean, for the field?
Thank you, Sally. So I'll dovetail off the gamma delta T cells. And we've seen some announcements. Recently today, actually from the Gamma Delta therapeutics and their ind and then at a set, obviously, Sally, as you mentioned, is presenting at ASCO and I'm very, very excited about the whole field of gamma delta T cells, because these cells come in different flavors that come as cytotoxic gamma Delta's which we've we're seeing now being leveraged by most of the companies, but then they also come in, in an immunosuppressive in a tumor promoting flavor. And what intrigues me here is that these cells may be amenable to allowing us to have an allergenic approach rather than autologous.
And the answer that you've just referred to, as talking about using Gamma Delta one, engineer T cells will glide pecan three specific car there is expressing soluble io 15 in liver cancer, and what I was really pleased to see is that as they're profiling these cells, because with gamma delta is one has to be really, really careful to phenotype and profile them very carefully, because they're they have such a high degree of plasticity. The cells being used here for therapy or having a phenotype defined by cd 45 are a positive cd 27 positive, and the immunosuppressive Gamma Delta one T cells, which is the other flavor of the same type, actually have an effector memory phenotype and, and many other different functional properties. So overall, very, very excited about the entire field of gamma delta T cells and looking forward to seeing those cell therapy trials read out. And then of course, we know that there are some antibody based plays in the field as well.
Maybe I'll touch upon a couple of targets that Umer mentioned, from a from a clinical standpoint, I was very intrigued by some data coming out around cd 47 in solid tumors, there's a concert of a very under the radar. Han x biopharmaceuticals doing a trial mean precise in Australia presenting at ASCO and they're doing this in solid tumors. It's actually a by a humanized by specific cd 47 pd one and they're enrolling really, really interesting tumor types colorectal breast, mesothelioma kalambo, pancreatic ovarian cancer, GBM, gastroesophageal Junction, and they've so far reporting. They're so far reporting on 18 patients. They're seeing three Partial responses and six stable diseases. And the responses are in qalandia, triple negative breast and in head and neck. So I'm really curious to follow them and see what happens with this study. And then another one, which was really interesting to me, we're all know about the challenge of cd 47 programs have had in solid tumors. But arch oncology is observing something interesting and managing it in an interesting way, which are the infusion related reactions. And I'm bringing this up from a clinical point of view. They are noticing quite a few of these and not mild ones by any means. And they're mitigating this by doing Of course, premedication within six hour long infusions to start with. So to me, this was a very interesting approach to mitigating IRR is and then tapering off steroids and shortening the infusions. But as we're all trying to move away from the fight a few pumps, this approach was very curious to me.
There were there was one interesting abstract I came across that I'd like to follow going forwards, it's gosmart bio, they have a first in class c 11 b acids, that is meant to decrease muscle derived suppressor cells, tumor associated macrophages convert M to M on macrophages and increase CD positive T cells in the tumors, and they also have a combination with pampering, a keynote, a 36 trial and a combination with Gemma Braxton in pancreatic. So I'm really curious to follow that one just because it's a play outside of T cells.
And then, I may want to just mention, Moroz data that they're showing with their empty body that is directed at energy fusion energy, one fusion positive patients. And they're showing some really, really interesting responses there. They've recruited 33 patients seeing an order of 27%. And specifically in pancreatic tumors, they're having four out of 10 responders, so 40%. And that, in addition to elevation and quality, who's have a pure heart to play for energy one fusions, it will be an interesting space to follow going forwards as far as I'm concerned.
Thank you. Yeah. Thanks, Alex. So we're going to transition to some broader themes. And actually, as we're doing this, I would like to ask, we're going to invite up some other experts from the audience. So there's a few people that I know I love to hear from. So we're going to talk just for another few minutes, and then we'll invite up some folks from the audience, please ping me if you want to come up. And if you have questions, but I'd like to direct the next sort of topic. And there's basically two topics that I want to talk about in terms of broader themes, one of which has to do with study design. And I've been struck by the disconnect between clinical trial design, which is optimized to get company programs to approval, versus what might be best for patients. And it's been interesting to see FDA is push now on minimum, minimally effective dose versus maximum tolerated dose, versus what would be ideal for market penetration. And I would love to hear from you, James, about where areas where we could better serve patients in our clinical trial design. And also, where is there a disconnect between study design and market penetration? Ultimately
Daphne, thank you so much. So, you know, I think this is an incredibly important area. I think one thing that I think everybody can agree on is we really need to understand the biology of the agent, that we're in the pathway that we're affecting, when we bring these things to the patients. And I think we probably do a good job at doing the the initial dose escalation studies and looking at the safety, but we don't as a field as a group, we don't always do a good job and in pharmacodynamic analysis, so I bring to point the efficacy stat, you know, the IDEO inhibitors were, you know, we knew how this worked preclinically we knew that what doses were safe, but we didn't really look in combination studies that what was going on with the the pathway that IDEO was was inhibiting as well as we shouldn't have. We didn't understand that as well, as we should have. Turns out probably under dosing patients, in part because of it. So that's one thing. I think another thing is, you know, we really need to end the early studies, we need to look at what is effective. Obviously, the goals are to find something that's going to be better than standard approaches when it comes to combination therapies.
I think that we have often done incremental combination approaches that may make sense maybe easier get to deconvolute, the, the, what is needed from each of the therapies and the relative contributions. But I think that there are opportunities here for rational combination approaches that really set the buyer bar higher for for effective treatments so that you can have a really high bar for efficacy. And if you get that great, if you don't, then that's your can be done quickly. And and move on. And the, I think the the seamless clinical trials where you have, instead of a phased approach with phase one, phase two, and phase three, that can be good. But the problem I see with that is often they've been used indiscriminately. And just to enroll many, many patients on without really having a clear understanding of the biology and what is good for those underlying patients just to see, is it going to work and kind of throwing spaghetti at the wall? I think we are.
I think that is not where we want to go with with that type of approach. And then finally, I would say that if we want to make more than just incremental advances, we want to take on the Goliath. So I in one way, you could say in retrospect, you know, Monday morning quarterbacking, that why oh, my goodness, you know, why did they take better fuse of alpha and go against Pember lism ab and PDL? One failures, did they want that trial to succeed? You know, why didn't they do what was done with some ipilimumab and just take, you know, versus chemotherapy and lung cancer and then you could get an answer and get a quick win.
I would argue, though, that if you want to be able to get that the use, you have to have a drug that's easy to use, you have to have a drug that has a clear advantage. And you know, when you're when you're going against the really the big guns in the field of PD one inhibition against you know, Pember lism ab, I think going head to head was a gutsy move that if it would have won would have won big. But because it didn't appear to win. And again, we're still going to wait to see the data. It's it'll be interesting, but it doesn't mean that it doesn't have activity. And I think that's where we need to be careful on how we how we look at these things.
Oh, by the way, there's a few experts in the audience that have come up that are going to come into the conversation. But if you're not speaking, can you go on mute? Especially Paul, you're not on mute. Thanks. Umer, Sally, do you guys have any comments that you'd like to make on that point? And Alex, and after that, I'd like to make sure we touch on financial toxicity. And of course, open it up to Bruce, we're really would love to hear from Chris and Paul joins us from the audience. Others please raise your hand if you want to join.
I was waiting and Sally wanted to speak first. I guess the only thing I would add is Look, if you if you are part of the reason this whole topic on minimum effective dose is coming up in a more prominent way now is we saw Amgen on their k Ras got feedback from FDA that you got to look into lower doses as well. And part of the reason is, look at Amazon's development on their k Ras molecule they have like three patient for patients that started at 180, then 360, then 720. And then we're at 960. I'm then all the expansion work happened at 960. However, if you ask me, what's the response rate on engines k Ras, I would say 35 40% in that range. Okay. Then if you ask me again, and again, by the way, this 35 40% is that 960 dose, then you asked me, What was the response rate at their lowest dose? Well, they had three patients at one at one of them responded. So that's one in three that's 33%. So how do we know what's the right dose? I think it's reasonable to say an FDA is bringing up a reasonable point that there's an attempt within oncology in particular where you're pushing for responses. And you're going to push the dose as much as you need to to get to that incremental response and not necessarily optimizing safety in Canada even just listening to the amazing panel here.
One of the big things I learned is look at how I started today's conversation with LaGG three I was so focused on comparing LaGG threes PFS in checkmate oh six seven versus how sorry ctla four is PFS in checkmate. oh six seven versus a has LaGG three track. But as Alex and James pointed out, it's tolerability is what they're seeing on a day to day basis when they're managing these patients. So If you look at it from that perspective, it all starts to tie in, if there really is making a concerted effort to encourage companies to look into lower doses, to sort of optimize for efficacy, safety balance, just like FDA does, by the way, and every other division, it's just oncology in particular, where everybody was chasing that last incremental response. So I'll pause there. And by the way, it's not a coincidence, we go back and look at the history of ctla four, for example, that used to be a drug that was supposed to be 10 milligrams per kilogram, and I'm sure some of the practitioners on our panel could speak to that. And now the dose is three in melanoma and one in lung and one every six weeks. It used to be 10 every three weeks, so I think it speaks to an improving appreciation for patient and tolerability. So
thanks, Umer. Do Bruce, Paul or Christopher want to comment on this topic of clinical trial design?
Okay. But I do have a couple of comments here, because I think it's a really important topic that's been in discussion with FDA for years now is how do we expand the patient population that are enrolling in phase one and phase two studies and eventually pivotal trials, but the conflict that exists, especially in Phase One is that if you enroll patient populations that in general are sicker, you oftentimes are going to be left with an uncertainty about attribution of adverse events. And that's a, it's a real challenge, because at the outset, you think you understand your mechanism, but oftentimes, you will observe things that you cannot be certain are or are not related to your drug. And as you as you go on, you may find that out. But especially in in today's world of sort of rapid information dissemination, the uncertainty around adverse event attribution, can submarine a program really quickly. So I understand the request. And it is actually my bias, to try to involve patients that need to, to find no therapies the most, but there is a major conflict for companies as they think about the risk there.
So maybe I can just add from a cell therapy perspective on the Advanced population, where in the autologous setting, the raw material is derived from the patient's own cells, and those who have undergone so many rounds of chemotherapy and immunotherapy, their cells are pretty beat up. And did it is a challenge. Other point I'll make is just as I'm an academic and involved in clinical trials, primarily in the early phase, we've been encouraged by hearing about the parent child ind concept, which I guess is equivalent to a basket trial, if you think about it, where you're going to have a parent ID in his process improvements or other changes are made or maybe swapping out a construct under the same ID, you can then add on, and perhaps just with some modifications to cohorts on the clinical trial, and, you know, the cycle of improvement, if there is a mismatch with the timing of the conduct of a clinical trial, and that potential modification in regulatory constructs as a possibility to help us I think,
thank you, Bruce. That's a great point.
So as we think about patients, you know, one of the things that I wanted to talk about is financial toxicity, if you think about the financial burden on cancer patients actually leads to worse outcomes. And the risk of dying from cancer was found to be vastly higher in cancer patients who filed for bankruptcy, for example. And, you know, we see then on the on the other side of the spectrum, a $16 billion market for checkpoint inhibitors, seven approved treatments, a sort of herd mentality around any new targets that are showing efficacy. So you know, it's really an without any significant price competition to date, for example. So it's really interesting to note that there are some new companies or companies that are now entering the field with a goal to really disrupt this and to provide much less expensive medicines. So I'd love to hear Umer maybe you can talk about how the price landscape might change. And then we'd love to hear from James, Alex and Sally as well as what kind of impact would that have in you know, the US for example, in the UK and other parts of the world.
If we start seeing real competition on pricing of some of these IO agents, so to you first. So, you know, I'm gonna date myself a little bit, I remember starting in my current job back in 2009, and updating a pricing file I used to keep across drug across drugs. And I remember updating a bunch of chemos and Tarceva and all these drugs, and they were all basically five to $6,000 a month. And that was pretty interesting. And they're all consistently between 12 and 15,000 a month. So there's, there's clearly been this shift. And by the way, short, that's more than doubled. But you know, what, I also used to keep a file on MS DOS therapies to in multiple sclerosis used to be 20 to 30k. And now there are 90k. So on a relative basis, the inflation in oncology has been less than other sectors. With that said, I do think it's really important. And I would be I would love to hear sort of, from the practitioners on the panel in the audience as well.
How you think about some fairly important changes coming up going forward, especially as it relates to financial talks, when you think about things like there's attempts being made by companies to bring lower cost PD wants to market for example, we know coherus, which is a biosimilar, new laughter manufacturer, they decided not to go the biosimilar route for PD ones. Instead, they in licensed a Chinese be one that they're going to develop in certification and launch. But I guess it is an open ended question that I would ask James and Alex and Sally's, well, would you use a PD one, if it only had data in for example, China, by the way, that's that Lily's about to do that. They're they're filing a PD one, which is approved in China data in lung cancer in China, would you use that data? reference it in us? Or conversely? What if, let's say I bring in a PD one hypothetically, and by the way, when I say I this is actually happening, let's say I bring in a PD one from China, let's say it's approved, and I have some data set in melanoma. James, would you use it in Jiyu? setting? For example, I'd love to hear.
So, you know, I think this is a great discussion. And I, you know, I have to be careful about not talking about too much on the financial end of things, but from the science end of things. As a clinician, I would like to see what the compatibility data is, certainly I'd like this, make sure that it's safe. And whatever the you know, the product was, was okay to, but the FDA will take care of the approval metrics with the product, but if if it is safe, and it has good comparability, in terms of its biologic, you know, if it binds to the same epitopes, if it if it has the same PK parameters, what are what's going to be the things that are going to then drive the decision to use that or we use something that we've already been using and have more comfort level with? And that is going to be what will be reimbursed? And what will be available for that patient? You know, most of the time for the oncology drugs, insurance companies will reimburse, and if there's a big copay, then there's often ways to get around that. But and it's less of an issue with infused drugs than it is with with oral drugs, for instance.
But you know, I think I think that, as a society, we have to be mindful of the continued pressure that the healthcare system is placed under with the with the rising cost and I think you're going to find that there's going to be more and more pressure to try and find innovative solutions and whether that's biosimilars, whether it's taking additional agents into the market, I think one of the reasons the FDA came up with five approvals in bladder cancer within a very short period of time with PD one and PDL, one inhibitors is because they wanted to get more market competitiveness and see if that could drive the cost of the drugs down. I'm I don't have any inside knowledge that of that. But I do think that that was one of the considerations that they had. And I think in the end, it came down more to which drugs could be given less frequently. Which drugs were the dogs more willing to use and that seemed to drive the market share. More
Thanks James. Alex?
Thank you, Daphne. So I completely agree with you, James. From my perspective, safety then becomes the first priority for any of these lower cost agents that we're potentially thinking about bringing in. But really, I practice in the UK, so the situation is slightly different than in the US. And there is a huge mismatch in terms of what drugs we can access and when on in the public sector versus the private sector. And if patients have private insurance, with any decent level of evidence, even from a phase two study for that particular indication, I can get a private insurer to approve and immunotherapy as a single agent or combo for that particular patient. There is absolutely no way that that will be feasible on the NHS. So if I can access a cheaper immunotherapy, let's call that tumor, an anti PD one that's from China, I will do that, yes, provided that it shows safety data, because really we're thinking about in clinic is if the patient's symptomatic, control the symptoms as quickly as possible, and then maintain quality of life and control that disease for as long as possible. Many of our oncology patients these days, are asymptomatic and have a very decent performance status in the metastatic setting. Front Line, right. So in that scenario, I want the least toxic drug that can keep the disease under control for the longest. And those seem to be immunotherapies. And sadly, we don't have them from line as much as we would want to orange as many indications as we would want to. So those would be my high level thoughts. And in terms of costs, again, we're now seeing that combinations may work better than single agents, which is not unexpected, but we're leaning towards triple quadruple combos. And that concerns me when it comes to both long term medical and financial talks. And I'm just going to also throw in a COVID wrench here, something that we've seen happen in the past year in oncology, we really have to get very, very creative in terms of dosing schedules. So I think we're have yet to see the impact of our creativity on patients revival. And I'm hoping that there will be a study that's going to be looking into this.
Great, thank you. So we're almost out of time. Unfortunately, we've got some great people who joined us from the audience in case they have additional comments. But I would love to just ask each of you to, to maybe make some closing remarks. I think Umer has to drop off right at one so maybe or you can go first.
Oh, I'm sorry. I missed the question. Oh, I'm ending it on a Hi.
I was at saying Do you want to make some closing remarks because you have to drop off first?
Yeah, I you know, I was gonna just mention um, I saw this thing in the ASCO abstract, a company animal who I'd never heard about. Bz d 9008. It's a EGFR exon 20 insert inhibitor. From a Chinese company. I think the founder is a former chemist from AstraZeneca. Some folks in the audience might even know him. 48% response rates. And he had two responses in patients that have taken the j&j antibody targeted at this in the grade three diarrhoea was 5% on this, unlike the Takeda molecule, which is like in the mid 20s. I thought that was a, it's an unusual sort of abstract, which got my attention. And clearly a lot of investors thinking about it to PRM 85 is another one, I think that emerging target, and perhaps even this rad 51 Media DNA repair inhibitor, which had a response in heme and solid tumor. So my point is, I feel like we kind of started with the conversation with targets, which perhaps weren't looking as exciting. But I do want to end with this hope and vision that there's a lot more therapeutics coming for cancer patients, and hopefully more tolerable ones and less financially toxic ones. So I'll leave it there.
Thanks so much, Umer. And then James, do you want to make some closing remarks? And I'll just thank everybody in advance, and some people have to drop off right at one and then we'll hear from Alex and Sally.
Sure. Thank you so much. So just real quick, I would say that, you know, this a has been really fun. So thanks so much for this. But I would say that as a field as a clinician, I can't be satisfied with just incremental advances. I want to see things that actually lead to a higher proportion of patients actually being cured. Because if you take that 45 year old or that 50 year old that can live now to nine years old. Really what difference is that a couple of months make it's really want to add in another, you know, 40 years? That's where we're going to see. And that's where I'd like to see the field. Find ways to say, Okay, this is where the cost benefit ratio comes in. And I'll just leave it there.
Thanks so much, James. Alex, Sally.
I'll be very quick. And I'm going to go into Thank you all and say that I hope we see each other in person at next year's ASCO in that madness of McCormick that I believe we're all missing out this year. And last year, thank you.
Thanks, Alex, Sally.
I get to end on a provocative note for everybody to think about. And goodbye to somebody to come in to their to math election change made earlier. I think one of the reasons that we sometimes don't Shi as good as results, as we might hope to see is that maybe sometimes the trial designs report, or should I say, not as optimal as they could be? Because we often go back to the time of phase one investigators who were used to property therapy and chemotherapy, but actually really don't understand the immune system. And a lot of the differentiation, trial design can sometimes come down to that, rather than the compounds themselves. So he some of my friends in industry who are listening in here, and I'd really like them to think about asking, and thinking about that a little bit more detail. Could we improve future outcomes and results are the result of better car designs? And I think that's something to think about. But otherwise, you know, I think I hope everybody had a great ask, go and enjoy the car over remote we might be and perhaps, you know, we may we'll be meeting up next year, whether it's after or as low and patch, the effects.
Thank you so much, Sally, and thanks to the terrific panel and for some of the audience members that were able to weigh in. We will try to get a recording of this and if we have one, we will make sure that you know how to access it. Thanks to everyone and have a great rest of your afternoon. Hope you have a great conference and we will now be closing the room. Thanks so much.
